Compositions of iodophenoxy alkanes and iodophenyl ethers in combination with cellulose derivatives for visualization of the gastrointestinal tract

ABSTRACT

Disclosed are x-ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising an iodophenoxy alkane, iodophenyl alkenylalkyl ether or an iodophenyl alkynylalkyl ether x-ray producing agent in combination with a cellulose derivative in a pharmaceutically acceptable carrier; and methods for their use in diagnostic radiology of the gastrointestinal tract.

This application is a continuation-in-part of application Ser. No.08/012,189 filed on Feb. 2, 1993, now U.S. Pat. No. 5,316,755.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to aqueous compositions containing the contrastagents iodophenoxy alkanes, iodophenyl alkenylalkyl ethers or iodophenylalkynylalkyl ethers and a cellulose derivative, and methods for theiruse in diagnostic radiology of the gastrointestinal tract.

2. Reported Developments

Roentgenographic examination utilizing x-rays and computed tomography(hereinafter CT) scans of fractures and other conditions associated withthe skeletal system is routinely practiced without the use of contrastagents. X-ray visualization of organs containing soft tissue, such asthe gastrointestinal (hereinafter GI) tract, requires the use ofcontrast agents which attenuate x-ray radiation. D. P. Swanson et al in"Pharmaceuticals In Medical Imaging", 1990, MacMillan PublishingCompany, provides an excellent background in medical imaging utilizingcontrast agents and compositions therewith.

Roentgenographic examination of the GI tract are indicated forconditions of digestive disorders, changes in bowel habit, abdominalpain, GI bleeding and the like. Prior to radiological examination,administration of a radiopaque contrast medium is necessary to permitadequate delineation of the respective lumen or mucosal surface fromsurrounding soft tissues. Accordingly, a contrast medium is administeredorally to visualize the mouth, pharynx, esophagus, stomach, duodenum andproximal small intestine. The contrast medium is administered rectallyfor examination of the distal small intestine and the colon.

The most widely used contrast agent for the visualization of the GItract is barium sulfate administered as a suspension orally or rectallyas an enema. (See, for example, U.S. Pat. Nos.: 2,659,690; 2,680,089;3,216,900; 3,235,462; 4,038,379 and 4,120,946) Notwithstanding itsrelatively good contrast characteristics, negligible absorption from theGI tract following oral or rectal administration and speedy excretionfrom the body, barium sulfate has certain disadvantages. In the presenceof intestinal fluids it lacks homogeneity and poorly adheres to mucusmembranes which can result in poor x-ray images. In the colon, whenadministered as an enema, it flocculates and forms irregular clumps withfecal matter.

Iodinated organic compounds have also been used as GI contrast agentssince the iodine atom is an effective x-ray absorber. They have the mostversatility and are utilized in the widest variety of procedures. Theyare very absorptive of x-rays with which the iodine interacts andproduce a so-called photoelectric effect which is a large magnificationin contrast caused by the photons stopped in the iodine-containingmedium. The magnification of contrast exceeds the level that would beexpected from relative changes in density. Because of thismagnification, relatively low concentrations of the contrast agent canbe utilized. (For iodinated agents see, for example, U.S. Pat. Nos.:2,786,055; 3,795,698; 2,820,814; 3,360,436; 3,574,718, 3,733,397;4,735,795 and 5,047,228.)

The desiderata for an ideal GI contrast agent includes: goodtoxicological profile; the ability to fill the entire bowel/lumen andevenly coat the gut mucosa so that the presence of the bowel isdetectable when the lumen is not distended; and nonirritation to theintestinal mucosa; and passage through the GI tract without producingartifacts or stimulating vigorous intestinal peristalsis.

These requirements were addressed by many investigators and theirefforts resulted in great improvements over the years. The requirementof evenly coating the gut mucosa with, and sufficiently adheringthereto, a contrast agent to effectively cover the walls of theintestines proved to be rather difficult. Without meeting theserequirements it is impossible to obtain x-ray pictures of highprecision. To that end, the use of certain polymer additives wereproposed as illustrated hereunder.

U.S. Pat. No. 4,069,306 discloses an x-ray contrast preparation which issaid to adhere to the walls of body cavities. The preparation comprisesa finely divided water-insoluble inorganic x-ray contrast agent andminute particles of a hydrophilic polymer which is insoluble in waterbut is water-swellable. The body cavity is supplied with suchpreparation suspended in water. The x-ray contrast agent is present inadmixture with and/or enclosed in and/or adhered to said minute polymerparticles.

U.S. Pat. No. 4,120,946 discloses a pharmaceutical composition forbarium opacification of the digestive tract, comprising colloidal bariumsulfate and a polyacrylamide in an aqueous vehicle. The polyacrylamideforms a viscous solution at low concentration which makes it possible tomaintain the barium sulfate in suspension and at the same time permitgood adherence of the preparation to the walls of the organ which it isdesired to x-ray.

U.S. Pat. No. 5,019,370 discloses a biodegradable radiographic contrastmedium comprising biodegradable polymeric spheres which carry aradiographically opaque element, such as iodine, bromine, samarium anderbium. The contrast medium is provided either in a dry or liquid stateand may be administered intravenously, orally and intra-arterially.

While these polymeric materials greatly enhance attachment of thecontrast agent used therewith to the walls of organs for bettervisualization thereof, there is still a need for an improved x-rayimaging medium that uniformly coats the soft tissues subjected todiagnostic x-ray examination.

SUMMARY OF THE INVENTION

It is the object of the present invention to provide compositions forcoating the gastrointestinal tract of mammals to form an effectiveradiopaque coating thereon by which diagnostic examination of the GItract may be accomplished. To that end, a thin coating is formed on theinner surface of the GI tract effected by ingesting, prior tovisualization by an x-ray emitting device, a cellulose derivative, whichhas incorporated therein an x-ray contrast agent, capable of coating theGI tract. Such compositions must meet several requirements: both thex-ray contrast agent and the cellulose derivative must be nontoxic; mustnot contain leachable or digestible components that would deleteriouslyaffect the patient; and no components of the coating should be absorbedby, and pass through, the inner surface of the intestine.

The contrast agent and the cellulose derivative are incorporated in aliquid media for administration to a mammal for x-ray visualization ofthe GI tract.

The contrast agent utilized in the present invention is represented bythe formula ##STR1## or a pharmaceutically acceptable salt thereofwherein Z is H, halo, C₁ -C₂₀ alkyl, cycloalkyl, lower alkoxy, cyano,where the alkyl and cycloalkyl groups can be substituted with halogen orhalo-lower-alkyl groups;

R is methyl, ethyl, propyl, C₉ -C₂₅ alkyl, cycloalkyl, orhalo-lower-alkyl, optionally substituted with halo, fluoro-lower-alkyl,aryl lower-alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl orlower-alkoxy-carbonyloxy,

(CR₁ R₂)_(p) --(CR₃ ═CR₄)_(m) Q, or (CR₁ R₂)_(p) --C.tbd.C--Q;

R₁, R₂, R₃ and R₄ are independently lower-alkyl, optionally substitutedwith halo;

x is 1-4;

n is 1-5;

m is 1-15;

p is 1-10; and

Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl,or aryl-lower alkyl.

As used herein, the term halogen (or halo) means fluorine, chlorine,bromine or iodine.

As used herein, the term cycloalkyl means carbocyclic rings having fromthree to eight ring carbon atoms including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cyclooctyl which may be substituted on anyring carbon atom thereof by one or more lower-alkyl groups, lower-alkoxygroups or halogens.

As used herein the terms lower-alkyl and lower-alkoxy mean monovalentaliphatic radicals, including branched chain radicals, of from one toten carbon atoms. Thus, the lower-alkyl moiety of such groups include,for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl,neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 2-hexyl, 3-hexyl, 1,1,3,3-tetramethylpentyl,1,1-dimethyloctyl and the like.

As used herein, the term lower-alkenyl and lower-alkynyl meansmonovalent, unsaturated radicals including branched chain radicals offrom three to ten carbon atoms and thus include 1-ethenyl,1-(2-propenyl), 1-(2-butenyl), 1-(1-methyl-2-propenyl),1-(4-methyl-2-pentenyl), 4,4,6-trimethyl-2-heptenyl, 1-ethynyl,1-(2-propynyl), 1-(2-butynyl), 1-(1-methyl-2-propynyl),1-(4-methyl-2-pentynyl) and the like.

As used herein, the term alkylene means divalent saturated radicals,including branched chain radicals of from two to ten carbon atoms havingtheir free valences on different carbon atoms and thus includes1,2-ethylene, 1,3-propylene, 1,4-butylene, 1-methyl-1,2-ethylene,1,8-octylene and the like.

As used herein, the term aryl means an aromatic hydrocarbon radicalhaving six to ten carbon atoms. The preferred aryl groups are phenyl,substituted phenyl and naphthyl substituted by from one to three, thesame or different members of the group consisting of lower-alkyl,halogen, hydroxy-lower-alkyl, alkoxy-lower-alkyl and hydroxy.

The x-ray contrast compound can comprise one, two, three or more iodineatoms per molecule; preferred species contain at least two, and morepreferably, at least three iodine atoms per molecule.

The solid x-ray contrast agents in particulate forms useful in thepractice of the present invention can be prepared by techniques known inthe art. The solid agents are comminuted to the desired size usingconventional milling methods, such as airjet or fragmentation milling.We have found that an effective average particle size of less than about100μ provides for good distribution and coating in the GI tract. As usedherein, particle size refers to a number average particle size asmeasured by conventional techniques, such as sedimentation field flowfractionation and disk centrifugation. An effective average particlesize of less than about 100μ means that at least about 90% of theparticles have a weight average particle size of less than about 100μ asmeasured by art recognized techniques.

The compositions may be in the form of suspensions or emulsions; weprefer to use emulsions as the preferred embodiment.

The cellulose derivative utilized in the present invention includesmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,hydroxyethylmethylcellulose, hydroxypropylmethylcellulose; andmicrocrystalline cellulose having an average particle size of from 0.01to 100μ, more preferably of from 0.05 to 10μ, and most preferably of 0.1to 1μ.

A method for diagnostic imaging of the GI tract for use in medicalprocedures in accordance with this invention comprises orally orrectally administering to the mammalian patient in need of an x-rayexamination, an effective contrast producing amount of a composition ofthe present invention. After administration at least a portion of the GItract containing the administered composition is exposed to x-rays toproduce an x-ray image pattern corresponding to the presence of thecontrast agent, then the x-ray image is visualized and interpreted usingtechniques known in the art.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the present invention can be made according to theschematic procedure shown or other methods using commercially availablestarting materials, intermediates and reagents. Starting materials,reagents and solvents can be obtained from chemical suppliers such asAldrich, Baker and Eastman Chemical Companies, or they may be preparedby techniques known in the art. ##STR2## wherein X=Halogen, OSO₂ CH₃

x=1-4

Z and R are as described above. ##STR3## wherein A=--(CR₃ ═CR₄)_(m) --

--C.tbd.C--

Y=Halogen, OSO₂ CH₃

x=1-4

and I_(n), Z, R₁, R₂, R₃, R₄ and Q are as described above.

The following examples will further illustrate the compounds used in thepresent invention.

EXAMPLE 1 2-(4-Iodophenoxy)-decane ##STR4##

To a solution of 2-decanol (5.0 ml, 26.0 mmol) in dry CH₂ Cl₂ (52 ml)under an N₂ atmosphere was added diisopropylethylamine (5.6 ml, 32.1mmol). The reaction flask was immersed in an ice/water bath. Afterstirring for 10 minutes, methanesulfonyl chloride (2.8 ml, 36.1 mmol)was added via syringe over a period of 10 minutes. After stirring for 3hrs, the reaction was diluted with cold CH₂ Cl₂ (200 ml) and poured intocold 5% aqueous HCl (100 ml). The layers were separated and the organicphase washed with cold 5% aqueous HCl (50 ml) followed by brine (2×50ml). The CH₂ Cl₂ layer was dried (Na₂ SO₄), filtered and evaporated invacuo at 25° C. The resulting light yellow oil was pumped under reducedpressure for 2 hrs to provide 2-methanesulfonyloxydecane (6.5 g, 93.5%)as a light yellow oil.

Without further purification, the above product (6.5 g, 24.3 mmol) wasdissolved in 50 ml dry N,N-dimethylformamide (DMF) with stirring.4-Iodophenol (4.8 g, 21.8 mmol) and potassium carbonate (3.4 g, 24.6mmol) were then added to the reaction flask which was immersed in an oilbath and heated to 57° C. over a period of 0.5 hr. After stirring for 14hrs under an N₂ atmosphere at 57° C., ¹ H NMR spectral analysisindicated about half of the mesylate was present. The temperature of theoil bath was increased to 66° C. and stirring continued. After anadditional 21 hrs, ¹ H NMR spectral analysis indicated that less than 5%of the mesylate remained. After stirring for a total of 37 hrs, thereaction was allowed to cool and filtered through a pad of celite withwashings of DMF to a total volume of 250 ml. The DMF layer was extractedwith hexanes (3×100 ml) and then diluted with 0.1M aqueous sodiumhydroxide. (250 ml). The mixed DMF/aqueous phase was extracted withhexanes (2×100 ml). The combined hexane washings were washedsuccessively with 1M aqueous sodium hydroxide (2×200 ml), water (2×200ml) and brine (2×200 ml), dried (Na₂ SO₄), filtered, and evaporated invacuo to provide a light yellow oil. This product was further purifiedby flash column chromatography (silica, hexanes) to yield2-(4-iodophenoxy)-decane (4.05 g, 51.6%) as a clear oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺, 360. Calculated forC₁₆ H₂₅ IO: C, 53.34; H, 6.99; I, 35.22. Found: C, 53.47, H, 6.99; I,35.43.

EXAMPLE 2 2-(2,4,6-Triiodophenoxy)-pentadecane ##STR5##

The 2-methanesulfonyloxypentadecane was prepared as follows: themesylate of 2-pentadecanol was prepared from 2-pentadecanol (25 g, 109mmol), methanesulfonylchloride (11.8 ml, 152 mmol) anddiisopropylethylamine (22.8 ml, 131 mmol) as previously described in 95%yield.

To a solution of 2-methanesulfonyloxypentadecane (15.5 g, 48.1 mmol) indry DMF (200 ml) was added triiodophenol (22.6 g, 47.9 mmol) andpotassium carbonate (6.6 g, 47.8 mmol). The reaction flask was immersedin an oil bath which was heated to 85° C. over a period of 0.5 hr. Thereaction was stirred under N₂ atmosphere for 16 hrs. At the end of thisperiod the reaction was processed as for Example 1 except at 4 times thevolumes to provide a brown residue. Flash column chromatography (silica,hexanes) provided 2-(2,4,6-triiodophenoxy)pentadecane (19.2 g, 58.8%) asa white solid. Mp: 56°-58° C.

Title Compound:¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₂₁ H₃₃ I₃ O: C,36.97; H, 4.88; I, 55.81. Found: C, 36.89, H, 4.80; I, 55.85.

EXAMPLE 3 2-(2,4,6-Triiodophenoxy)decane ##STR6##

The 2-methanesulfonyloxydecane (14.8 g, 62.6 mmol), 2,4,6-triiodophenol(29.7 g) 62.9 mmol) and potassium carbonate (8.7 g, 63.0 mmol) werereacted in DMF (210 ml) as per 2-(2,4,6-triiodophenoxy)-pentadecaneexcept at an oil bath temperature of 72° C. for 88 hrs. The reaction wasprocessed as for 2-(2,4,6-triiodophenoxy)-pentadecane to provide a lightbrown residue. Flash column chromatography (silica, hexanes) provided2-(2,4,6-triiodophenoxy)-decane (29.1 g, 75.9%) as a white solid.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₆ H₂₃ I₃ O: C,31.40; H, 3.79; I, 62.20. Found: C, 31.50, H, 3.75; I, 62.37.

EXAMPLE 4 (2,4,6-Triiodophenoxy)-1H,1H,2H,2H-perfluorooctane ##STR7##

A mixture of 3.00 g (8.24 mmol) of 1H,1H,2H,2H-perfluorooctanol and 1.28g (9.89 mmol) of N,N-diisopropylethylamine in 12 ml of drydichloromethane was placed under nitrogen and cooled to 0° C.Methanesulfonyl chloride (1.04 g, 9.06 mmol) was added dropwise viasyringe and the resulting solution was stirred at 0° C. for 1.5 hrs. Themixture was partitioned between 100 ml of dichloromethane and 100 ml of1M HCl. The dichloromethane layer was then washed with water (100 ml)and brine (100 ml). The solution was dried over Na₂ SO₄ and concentratedin vacuo to afford 3.28 g (90%) of the mesylate as a white solid.

A mixture of 2.11 g (4.77 mmol) of the above mesylate, 1.50 g (3.18mmol) of 2,4,6-triiodophenol and 0.75 g (5.41 mmol) of potassiumcarbonate in 5 ml of dry DMF was stirred and heated to 80° C. undernitrogen for 40 hrs. The mixture was cooled and partitioned between 100ml of ethyl acetate and 100 ml of 1M HCl. The ethyl acetate layer wasthen washed with water (50 ml) and brine (25 ml). The brown solution wasdried over Na₂ SO₄ and concentrated in vacuo to yield a brown solid(1.89 g). The brown solid purified by flash chromatography (silica gel,hexanes) affording 1.35 g (52%) of the pure product. Mp: softens at55°-58° C., melts at 63° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS; (M+1)⁺ 818. Calculatedfor C₁₄ H₆ F₁₃ O₃ O: C, 20.56; H, 0.74. Found: C, 20.75; H, 0.69.

EXAMPLE 5 1-(2,4,6-Triiodo-3-trifluorophenoxy)octane ##STR8##

A mixture of 0.540 g (1.00 mmol) of 2,4,6-triiodo-3-trifluoromethylphenol, 0.691 g (5.00 mmol) of potassium carbonate and 0.212 g (1.10mmol) of 1-bromooctane in 3 ml of dry acetonitrile was heated to refluxunder nitrogen and stirred for 3.5 hrs. The mixture was cooled andpartitioned between 50 ml of water and 75 ml of ethyl acetate. The ethylacetate layer was then washed with brine (20 ml), dried over Na₂ SO₄ andconcentrated in vacuo to 0.645 g of yellow oil. The oil was purified byflash chromatography on 25 g of silica gel with hexane as the eluent togive 0.498 g (76%) of a colorless oil which crystallized to a whitesolid on standing. Mp. 39°-42° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: (M-1)⁺ 651. Calculatedfor C₁₅ H₁₈ F₃ I₃ : C, 27.63; H, 2.78; I, 58.34. Found: C, 28.11; H,2.78; I, 57.11.

EXAMPLE 6 2-(2,4,6-Triiodophenoxy)-nonane ##STR9##

The 2-methanesulfonyloxynonane (22.8 g, 102 mmol), triiodophenol (48.8g, 103 mmol) and potassium carbonate (14.2 g, 103 mmol) were reacted inDMF (206 ml) as per 2-(2,4,6-triiodophenoxy)pentadecane except at an oilbath temperature of 82° C. for 14 hrs. The reaction was processed as for2-(2,4,6-triiodophenoxy)pentadecane to provide a light brown oil. Flashcolumn chromatography (silica, hexanes) provided2-(2,4,6-triiodophenoxy)nonane (40.8 g, 68.0%).

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₅ H₂₁ I₃ O: C,30.13; H, 3.54; I, 63.66. Found: C, 30.52, H, 3.49; I, 63.47.

EXAMPLE 7 2-Ethyl-1-(2,4,6-triiodophenoxy)-hexane ##STR10##

2-Ethyl-bromohexane (10.4 g, 53.0 mmol), triiodophenol (25.5 g, 54.0mmol) and potassium carbonate (7.5 g, 54.3 mmol) were reacted in dry DMF(110 ml) at 77° C. as for 2-(2,4,6-triiodophenoxy)butane. After stirringfor 20 hrs, the reaction was cooled, diluted with DMF, filtered througha pad of celite and evaporated in vacuo. The resulting residue was takenup in EtOAc (500 ml), washed with water (200 ml), 1N aqueous sodiumhydroxide (200 ml), water (2×200 ml) and brine (200 ml), dried (Na₂SO₄), filtered and evaporated. Flash column chromatography (silica,hexanes) provided 2-ethyl-1-(2,4,6-triiodophenoxy)-hexane (22.8 g,73.7%) as a clear viscous oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₁₉ I₃ O: C,28.79; H, 3.28; I, 65.19. Found: C, 29.13, H, 3.24; I, 65.05.

EXAMPLE 8 3,3-Diphenyl-1-(2,4,6-triiodophenoxy)propane ##STR11##

A mixture of 2,4,6-triiodophenol (0.78 g, 1.65 mmol) and potassiumcarbonate (0.25 g, 1.82 mmol, 1.1 eq) in 5 ml of dimethylformamide washeated at 60° C. for 1 hr, cooled and then 3,3-diphenylpropyl bromide(0.5 g, 1.82 mmol) was added. After stirring for 30 minutes at roomtemperature the mixture was heated at 60° C. for 24 hrs. The mixture wasthen cooled, poured into water and the crude product was isolated byethyl acetate extraction. The product was purified by silica gelchromatography (2.5% ethyl acetate-hexanes) followed byrecrystallization from hexanes to give 0.53 g (48%) of a solid. Mp:120°-121° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₂₁ H₁₇ I₃ O: C,37.87; H, 2.57; I, 57.66. Found: C, 37.95; H, 2.60; I, 57.11.

EXAMPLE 9 3-(2,4,6-Triiodophenoxy)-nonane ##STR12##

The mesylate of 3-nonanol was prepared in the usual manner form3-nonanol (7.5 g, 52 mmol), diisopropyl ethylamine (11.7 ml, 67 mmol)and methane sulfonyl chloride (4.8 ml, 62 mmol) in dry CH₂ Cl₂ (104 ml).

The mesylate of 3-nonanol (11.5 g, 51.9 mmol), triiodophenol (24.5 g,51.9 mmol) and potassium carbonate (7.18 g, 51.9 mmol) were reacted indry DMF (200 ml) as per 2-(2,4,6-triiodophenoxy)-pentadecane except atan oil bath temperature of 87° C. for 16 hrs. The reaction was processedas for 2-(2,4,6-triiodophenoxy)-pentadecane to provide a light brownoil. Flash column chromatography (silica, hexanes) provided3-(2,4,6-Triiodophenoxy)nonane (20.9 g, 67%) as a clear viscous oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS M⁺ 598. Calculated for C₁₅H₂₁ I₃ O: C, 30.13; H, 3.54; I, 63.66. Found: C, 30.54, H, 3.51; I,63.58.

EXAMPLE 10 2-(4-Iodophenoxy)-undecane ##STR13##

2-Methanesulfonyloxyundecane was prepared as described for2-methanesulfonyloxydecane from 2-undecanol (30.0 ml, 144 mmol),methanesulfonylchloride (15.5 ml, 200 mmol) and diisopropylethylamine(30.8 ml, 177 mmol) in dry CH₂ Cl₂ (240 ml). After stirring for 3.5 hrs,the reaction was processed as previously stated but at 4 times thevolumes to provide 2-methanesulfonyloxyundecane (31.35 g, 95%).

The above product (31.3 g, 136.7 mmol) was reacted with 4-iodophenol(30.1 g, 136.8 mmol), and potassium carbonate (18.9 g, 136.7 mmol) inDMF (270 ml) at 80° C. as for 2-(4-iodophenoxy)decane. After stirringfor 13 hrs, the reaction was analyzed by ¹ H NMR indicating that thereaction was about 66% complete. The temperature of the oil wasincreased 84° C. After an additional 34 hrs, ¹ H NMR spectral analysisindicated that the reaction was complete. The reaction was processed asfor 2-(4-iodophenoxy)-decane except at 2 times the volume to give alight yellow oil. This product was further purified by flash columnchromatography (silica, hexanes) to give 2-(4-iodophenoxy)-undecane(16.1 g, 31%) as a clear oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺, 374. Calculated forC₁₇ H₂₇ IO: C, 54.55; H, 7.27; I, 33.90. Found: C, 54.75, H, 7.32; I,33.97.

EXAMPLE 11 2-Iodophenoxycyclopentane ##STR14##

A mixture of 2-iodophenol (8.0 g, 36.4 mmol), milled potassium carbonate(5.5 g, 39.9 mmol, 1.1 eq) and 1-bromocyclopentane bromide (3.9 ml, 36.4mmol) in 25 ml of N,N-dimethylformamide was heated at 120° C. for 1.1hrs and cooled. The mixture was poured into water and extracted twicewith ether. The ether layer was dried over magnesium sulfate, filtered,and concentrated to give an oil. The crude product was dissolved inethyl acetate and filtered through a short pad of silica gel. Thefiltrate was redried over magnesium sulfate, filtered and concentratedunder vacuum to give 10 g (95%) of product as an oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₁ H₁₃ IO: C,45.85; H, 4.55; I, 44.04. Found: C, 45.78; H, 4.51; I, 43.88.

EXAMPLE 12 3-Iodophenoxycyclopentane ##STR15##

Using the same procedure as in the preparation of2-iodophenoxycyclopentane, 3-iodophenoxycyclopentane was prepared in 68%yield from 3-iodophenol (9.9 g, 45.4 mmol), potassium carbonate (6.9 g,49.9 mmol, 1.1 eq) and cyclopentyl bromide (5.4 ml, 49.9 mmol, 1.1 eq).The crude product was isolated by ethyl acetate extraction andfiltration through a pad of basic alumina affording the pure product asan oil after concentration under high vacuum.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₁ H₁₃ IO: C,45.85; H, 4.55; I, 44.04. Found: C, 46.03; H, 4.46; I, 44.12.

EXAMPLE 13 (3,5-Dimethyl-2,4,6-triodophenoxy)cyclopentane ##STR16##

A mixture of 3,5-dimethyl-2,4,6-triiodophenol (4.0 g, 8 mmol),cyclopentyl bromide (1.0 ml, 9.6 mmol, 1.2 eq), and potassium carbonate(1.33 g, 9.6 mmol, 1.2 eq.) in N,N-dimethylformamide (30 ml) was stirredat room temperature overnight. The mixture was poured into water andextracted first with ethyl acetate and then dichloromethane. Thecombined organic extracts were dried over magnesium sulfate and strippedto give a gum. The crude product was dissolved in ethyl acetate andfiltered through a pad of silica gel and then through a pad of basicalumina. The filtrates were combined, concentrated and the product wasthen isolated (56% yield) by silica gel chromatography (hexanes) to givea viscous oil which solidified under high vacuum. Mp. 68°-80° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₃ H₁₅ I₃ O: C,27.49; H, 2.66; I, 67.03. Found C, 27.76; H, 2.62; I, 65.65.

EXAMPLE 14 2-(4-Iodophenoxy)-pentadecane ##STR17##

The 2-methanesulfonyloxypentadecane was prepared from 2-pentadecanol (25g, 109 mmol), methanesulfonylchloride (11.8 ml, 152 mmol) anddiisopropylethylamine (22.8 ml, 131 mmol) as previously described in 95%yield.

The 2-methanesulfonyloxypentadecane (34.4 g, 102 mmol) was reacted with4-iodophenol (22.7 g, 103 mmol) and potassium carbonate (14.3 g, 103mmol) in DMF (200 ml) as per 2-(4-iodophenoxy)decane except that thetemperature of the oil bath was maintained at 80° C. for 15 hrs andincreased to 86° C. with stirring for an additional 24 hrs. At the endof this period, NMR spectral analysis indicated that the reaction wascomplete. The reaction mixture was processed as for2-(4-iodophenoxy)decane except with four times the volumes to provide alight yellow oil. Flash column chromatography (silica, hexanes) yielded2-(4-iodophenoxy)pentadecane (18.9 g, 43.0%) as a clear oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺, 430. Calculated forC₂₁ H₃₅ IO: C, 58.47; H, 8.41; I, 29.42. Found: C, 58.91, H, 8.36; I,29.26.

EXAMPLE 15 4-Iodophenoxycyclopentane ##STR18##

Using the procedure described for 2-iodophenoxycyclopentane,4-iodophenoxycyclopentane was prepared in 80% yield from 4-iodophenol(4.0 g, 18.2 mmol), cyclopentyl bromide (1.95 ml, 18.2 mmol, 1 eq) andpotassium carbonate (2.76 g, 20 mmol, 1.1. eq) in 25 ml ofdimethylformamide after ether extraction and filtration through basicalumina. The pure product was obtained as a solid (mp 50°-52° C.) aftercrystallization from hexanes.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₁ H₁₃ IO: C,45.85; H, 4.55; I, 44.04. Found: C, 45.90; H, 4.48; I, 44.13.

EXAMPLE 16 2,4,6-Triiodophenoxycyclopentane ##STR19##

Milled, anhydrous potassium carbonate (14.2 g, 103 mmol, 1.2 eq) wasadded in portions to a stirred solution of 2,4,6-triiodophenol (40.5 g,85.8 mmol) in 50 ml of dry (4A sieves) dimethylformamide at roomtemperature. After stirring for 20 minutes, cyclopentyl bromide (12 ml,112 mmol, 1.3 eq) in dimethylformamide (20 ml) was added and the viscousmixture was gradually heated to 130° C. under argon for approximately 45minutes. After cooling, the mixture was filtered and the collected solidwas washed with chloroform. The filtrate was concentrated in vacuo togive 50 g of an amber oil The crude oily product was partitioned betweenethyl acetate (300 ml) and water (500 ml); the organic layer was driedover magnesium sulfate and passed through a short pad of silica gel. Thefiltrate was treated with decolorizing carbon, filtered, and stripped togive an amber oil. The oil was dried at 60° C. under high vacuum to give40.4 g (87%) of product.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. MS: M⁺ 540; Calculated for C₁₁H₁₁ I₃ O: C, 24.47; H, 2.05; I, 70.51. Found: C, 24.42; H, 1.98; I,70.58.

EXAMPLE 17 2,4,6-Triiodophenoxymethylcyclopentane ##STR20##

A stirred mixture of 36.2 g (0.08 mol) of 2,4,6-triiodophenol, 12.5 g(0.08 mol) of bromomethylcyclopentane [Noller and Adams, J. Org. Chem.,48, 1080-9 (1926)] and 10.6 g (0.08 mol) of milled anhydrous potassiumcarbonate in 100 ml dry dimethylformamide was heated at 100° C. underargon for 3.5 hrs. The mixture was cooled and concentrated in vacuo. Theresulting residue was combined with 100 ml of ice-cold water and theoily product was extracted with ethyl acetate (3×100 ml). The combinedethyl acetate extracts were dried (MgSO₄) and concentrated in vacuo to adark oil. The oil was purified by chromatography (neutral alumina elutedby hexanes) to yield 24.0 g (57%) of the desired product as an oil. Bp:220°-5° C./1 atm.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺ 553; Calculated forC₁₂ H₁₃ O: C, 26.02; H, 2.37; I, 68.73. Found: C, 26.33; H, 2.37; I,68.47.

EXAMPLE 18 2-(2,4,6-Triiodophenoxy)ethylcyclopentane ##STR21##

Methanesulfonyl chloride (2.72 ml, 35.1 mmol, 1.1 eq) was added dropwiseover a period of several minutes to a cooled (ice/methanol) and stirredsolution of 2-cyclopentylethanol (3.64 g, 31.9 mmol) and triethylamine(6.23 ml, 47.9 mmol, 1.5 eq) in 200 ml of dry (4A molecular sieves)dichloromethane under an argon atmosphere. After stirring for severalminutes, a white precipitate formed and the mixture was stirred anadditional 30 minutes. The reaction mixture was washed successively withwater, 10% aqueous hydrochloric acid, saturated aqueous sodiumbicarbonate, saturated sodium chloride and then dried over magnesiumsulfate. The organic layer was filtered and concentrated under vacuum togive 5.87 g (95%) of the methanesulfonate ester as a pale yellow liquidwhich was stored in the cold and used without further purification. ¹H-NMR (300 MHZ) spectral data was consistent with the desired product.CI/MS: M⁺ 193.

To a stirred mixture of 2,4,6-triiodophenol (20.36 g, 43.2 mmol) andmilled anhydrous potassium carbonate (7.2 g, 52.2 mmol) in 75 ml of drydimethylformamide was added dropwise over 10 minutes, a solution of2-cyclopentylethylmethanesulfonate (8.2 g, 42.7 mmol) in 10 ml ofdimethylformamide. The mixture was heated at 65° C. under argonovernight and the solvent was then removed under vacuum. The resultingamber residue was partitioned between ethyl acetate (200 ml) and water(30 ml). The aqueous layer was further extracted with ethyl acetate(2×250 ml) and the combined ethyl acetate extracts were treated withdecolorizing carbon, dried over magnesium sulfate and passed through ashort pad of basic alumina. The filtrate was evaporated under vacuum togive 17.5 g (73%) of the desired product as an amber oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺ 568; Calculated forC₁₃ H₁₅ I₃ O: C, 27.49; H, 2.66; I, 67.03. Found: C, 27.42; H, 2.62; I,66.74.

EXAMPLE 19(E,E)-1-(2,4,6-Triiodophenoxy)-3,7,11-trimethyl-2,6,10-dodecatriene##STR22##

A mixture of triiodophenol (17.3 g, 36.8 mmol), farnesyl bromide (10 g,35 mmol) and potassium. carbonate (5.0 g, 36.2 mmol, 1.05 eq) in 40 mlof N,N-dimethylformamide was heated at 80°-100° C. for 3 hrs. Themixture was cooled and poured into water whereupon an oil precipitatedafter briefly stirring rapidly. The bulk of the water was decanted andthe residue was take up in dichloromethane. The organic layer was washedwith water, dried over magnesium sulfate and filtered through a pad ofsilica gel. The combined filtrate was concentrated under vacuum leavingthe crude farnesyl ether derivative which was purified by silica gelchromatography (hexanes/ethyl acetate 9:1) to give the desired productas an oil in 41% yield.

Title Compound: ¹ H (300 MHz) and ¹³ C (7.5 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₂₁ H₂₇ O₃ O: C,37.36; H, 3.88; I,56.39. Found: C, 37.68; H, 3.95; I, 55.97.

EXAMPLE 20 1-(2,4,6-Triiodophenoxy)-3,7-dimethyl-6-octene ##STR23##

To a stirred solution of citronellol (4.5 g, 28.8 mmol) andtriethylamine (5.2 ml, 34.6 mmol, 1.2 eq) in dichloromethane (50 ml)cooled to 0° C. was added dropwise, a solution of methanesulfonylchloride (2.46 ml, 28.8 mmol) in dichloromethane (50 ml). The solutionwas stirred for 1hr at 0° C. under nitrogen and then water was added.The dichloromethane layer was dried over magnesium sulfate after washingwith saturated aqueous sodium chloride and then concentrated in vacuo togive an oil. ¹ H-NMR (300 MHZ) spectrum of the oil indicated the desiredmethanesulfonate ester. The methanesulfonate ester was added to astirred mixture of 2,4,6-triiodophenol (13.6 g, 28.8 mmol) and potassiumcarbonate (4.0 g, 28.8 mmol) in dimethylformamide (50 ml). The mixturewas heated to 100° C. for 30 minutes and cooled to room temperature. Thecrude product was isolated by partitioning the reaction mixture betweenwater and dichloromethane. The organic layer was concentrated undervacuum to give an oil. The oil was purified by flashing through basicalumina with hexanes to give the desired product in 15% yield as alight-sensitive oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₆ H₂₁ I₃ O: C,31.50; H, 3.47; I, 62.41. Found: C, 31.71; H, 3.41; I, 62.30.

EXAMPLE 21(E)-1-(3,5-Dimethyl-2,4,6-triiodophenoxy)-3,7-dimethyl-2,6-octadiene##STR24##

Using the procedure described for the synthesis of(E)-(2,4,6-triiodophenoxy)-3,7-dimethyl-2,6-octadiene,(E)-1-(3,5-dimethyl-2,4,6-triiodophenoxy)-3,7-dimethyl-2,6-octadiene wasprepared in 37% yield from 3,5-dimethyl-2,4,6-triiodophenol (2.0 g, 4.0mmol), geranyl bromide (0.87 g, 4.0 mmol) and potassium carbonate (0.55g, 4.0 mmol) in 20 ml of dimethylformamide. Recrystallization fromhexanes afforded analytically pure product. Mp 65°-66° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₈ H₂₃ I₃ O: C,33.99; H, 3.64; I, 59.85. Found: C, 34.15; H, 3.58; I, 59.84.

EXAMPLE 22 (E)-1-(2,4,6-triiodophenoxy)-3,7-dimethyl-2,6-octadiene##STR25##

A mixture of triiodophenol (10.0 g, 21.2 mmol), milled potassiumcarbonate (3.1 g, 22.5 mmol, 1.06 eq) and geranyl bromide (4.0 ml, 20.2mmol) in dimethyl formamide (25 ml) was heated to 50° C. for 2 hrs andcooled. The mixture was poured into 300 ml of water and extracted withethyl acetate. The ethyl acetate extract was filtered through a shortpad of silica gel, then alumina, eluting with ethyl acetate-hexanes(1:1). The eluent was concentrated under high vacuum to give the productin 87% yield as an oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₆ H₁₉ I₃ O: C,31.61; H, 3.15; I, 62.61. Found: C, 31.84; H, 3.06; I, 62.60.

EXAMPLE 23 1-(2,4,6-Triiodophenoxy)-3-octyne ##STR26##

A mixture of triiodophenol (1.0 g, 2.1 mmol) and potassium carbonate(0.35 g, 2.54 mmol, 1.2 eq) in 4 ml of dimethylformamide was heated at70° C. for 1 hr and then cooled to room temperature. 1-bromo-3-octynewas added in a single portion and the mixture was stirred for 1 hr. Thereaction mixture was poured into water and the precipitated solids werecollected by filtration. The collected solid was recrystallized frommethanol to give 0.39 g (32%) of desired product. Mp 45° C.-49° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₁₅ I₃ O: C,28.99; H, 2.61; I, 65.64. Found: C, 28.92; H, 2.49; I, 65.67.

EXAMPLE 24 2-(2,4,6-Triiodophenoxy)-4-octyne ##STR27##

To a cooled solution of 4-octyn-2-ol (5.0 g, 39.6 mmol) in pyridine (40ml) at -10° C. (ice/salt) was added dropwise methanesulfonyl chloride(4.6 ml, 59.4 mmol, 1.5 eq.) and the solution was stirred for 2.5 hrs.The reaction mixture was poured into water (25 ml) and extracted withdichloromethane. The organic layer was washed with 2N aqueoushydrochloric acid, saturated aqueous sodium bicarbonate and dried overmagnesium sulfate. The organic layer was filtered and evaporated to givean oil (8.48 g, quantitative yield) which was stored in the freezer andused without further purification. ¹ H-NMR (300 MHZ) spectral data wasconsistent with the desired methanesulfonate ester.

A mixture of 2,4,6-triiodophenol (10.9 g, 23.1 mmol) and potassiumcarbonate (3.51 g, 25.4 mmol) in dimethylformamide (45 ml) was heated at70° C. for 2.5 hrs and a solution of (4-octyn-2-yl)-methanesulfonate(6.12 g, 30.0 mmol, 1.3 eq.) in a minimum amount of dimethylformamidewas added. The mixture was then heated to 110° C. overnight. Aftercooling the reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with water several times anddried over magnesium sulfate, filtered and concentrated to an oil.Silica gel chromatography (1% ethyl acetate-hexanes) gave 6.48 g, (48%)of the product as a yellow-orange oil. Additional filtration throughsilica gel gave colorless material.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₁₅ I₃ O: C,28.99; H, 2.61; I,65.64. Found: C, 29.23; H, 2.53; I, 65.45.

EXAMPLE 25 1-(2,4,6-Triiodophenoxy)-3-octyne ##STR28##

Triphenylphosphonium dibromide (36.8 g, 87.2 mmol) was suspended indiethyl ether at -20° C. and a solution of 3-octyne-1-ol (10.0 g, 79.2mmol) was added dropwise over a twenty minute period. The mixture wasallowed to stir overnight. The mixture was poured into ice-water andsolids precipitated which were collected by filtration. The organiclayer was separated, washed with 1N aqueous sodium hydroxide, water anddried over magnesium sulfate. The organic layer was then filtered andconcentrated in vacuo to give a residue which was taken up in hexanes,filtered to remove undissolved material and concentrated to give1-bromo-3-octyne as an orange oil (14.2 g, 96%). ¹ H NMR (300 MHZ)spectral data were consistent with the desired bromide (plus a trace oftriphenylphosphine), and the crude product was used directly in the nextstep.

A mixture of 2,4,6-triiodophenol (1.0 g, 21 mmol) and potassiumcarbonate (351 mg, 2.54 mmol) in dimethylformamide (4 ml) was heated at60° C. for 1 hour and then 1-bromo-3-octyne (0.4 g, 2.1 mmol) was added.After heating for an additional hour the mixture was stirred at roomtemperature for 72 hours. The reaction was poured into water and theprecipitated solids were collected to give the crude product. The crudeproduct was recrystallized from methanol to give 0.24 g (50%) of theoctynyl ether, mp 79°-81° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₁₅ I₃ O: C,28.99; H, 2.61; I,65.64. Found: C, 29.05; H, 2.53; I, 65.92.

EXAMPLE 26 Diethyl 2-(2,4,6-Triiodophenoxy)-1,3-propanedioate ##STR29##

A stirred mixture of 70.8 g (0.15 mol) of 2,4,6-triiodophenol, 39.0 g(0.15 mol) of diethyl bromomalonate and 20.7 g (0.15 mol) of milledanhydrous potassium carbonate in 200 ml of dry dimethylformamide washeated at 100° C. under argon for 5 hours. The mixture was cooled andconcentrated in vacuo. The resulting residue was combined with 300 ml ofice-cold water and the oily product was extracted with ethyl acetate(1×300 ml), 3×100 ml). The combined ethyl acetate extracts were dried(MgSO₄) and concentrated in vacuo to a dark oil. The oil was purified bychromatography (eluted by hexanes to 20% diethyl ether in hexanes) toyield 60.2 g (64%) of product as a light cream-colored solid.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺ 631; Calculated forC₁₃ H₁₃ I₃ O₅ : C, 24.79; H, 2.08; I, 60.44. Found: C, 25.07; H, 2.00;I, 60.09.

EXAMPLE 27 Diisopropyl 2-(2,4,6-Triiodophenoxy)-1,3-propanedioate##STR30##

A stirred solution of 18.8 g (0.1 mol) of diisopropyl malonate in 100 mlcarbon tetrachloride was cooled in an ice bath and 15.8 g (0.1 mol)bromine was added dropwise over a 90 minute period. The ice bath wasremoved and the reaction stirred at room temperature for 20 hours. Thereaction solution was concentrated in vacuo and the resulting residuedistilled to yield 16.1 g (76%) of the bromomalonate I [H. P. Gallus andA. K. Macbeth, J. Chem. Soc., 1937, 1810-12] as a dear colorless liquid;Bp 51°-2° C./0.1 mm Hg. CI/MS: MR⁺ 267. ¹ H-NMR (300 MHZ) spectral datawas consistent with the desired structure. Using the same procedure asfor 2-(2,4,6-triiodophenoxy)-1,3-propanedioic acid, diethyl ester, butsubstituting methylene chloride for ethyl acetate in the aqueousextraction, 2-(2,4,6-triiodophenoxy)-1,3-propanedioic acid, diisopropylester was prepared from 8.6 g (0.03 mol) of malonate I, 107 g (0.03 mol)of 2,4,6-triiodophenol, 4.5 g (0.03 mol) of milled anhydrous potassiumcarbonate and 30 ml of dimethylformamide in 69% yield as a tan oil;bp>65° C./0.65 mm Hg after chromatography (hexanes to 5% ether inhexanes).

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: MH+ 659. Calculated forC₁₅ H₁₇ I₃ O₅ : C, 27.38 H, 2.60; I, 57.86. Found: C, 27.45; H, 2.56; I,57.82.

EXAMPLE 28 Ethyl-2,2-Bis-(3-iodophenoxy)acetate ##STR31##

A stirred solution of 40.0 g (0.18 mol) of 3-iodophenol, 33.6 ml (0.18mol) of diethyl bromomalonate and 27.63 g (0.2 moles) of milledanhydrous potassium carbonate in 250 ml dry N,N-dimethylformamide washeated at 110°-120° C. under argon for 14 hours. The mixture was cooledand concentrated in vacuo. The resulting residue was combined with 600ml of ice-cold water and the oily product was extracted with ethylacetate (4×150 ml). The combined ethyl acetate extracts were dried(MgSO₄) and concentrated in vacuo to an orange oil. The orange oil waspurified by chromatography (eluted by 5% methylene chloride in hexanesto 50% methylene chloride in hexanes) to yield 8.1 g (8.5%) of thedesired product as a tan oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺ 524. Calculated forC₁₆ H₁₄ I₂ O₄ : C, 36.67 H, 2.69; I, 48.43. Found: C, 36.92; H, 2.65; I,48.24.

EXAMPLE 29 Ethyl 5-(2,4,6-triiodophenoxy)hexanoate ##STR32##

To a solution of ethyl 5-oxo-hexanoate (23.8 g, 150 mmol) in THF (270ml) was added methanol (30 ml). The reaction flask was immersed in anice/water bath and sodium borohydride (2.3 g, 60.8 mmol) was added. Thereaction was stirred for 16 hrs with warming. At this point more sodiumborohydride (2.3 g, 60.8 mmol) was added to the reaction flask. After aperiod of 2 hrs, the reaction was poured into a stirred mixture ofcrushed ice (250 g), saturated aqueous ammonium hydroxide (250 ml) andether (500 ml). After stirring for 2 hrs, the organic phase wasseparated. The aqueous phase was extracted with EtOAc (2×200 ml). Theorganic washings were dried (Na₂ SO₄), filtered an evaporated in vacuoto provide a light yellow solid (22.2 g). The product was purified byflash column chromatography (silica, 1:4, ethylacetate:hexanes) to giveethyl 5-hydroxyhexanoate (20.3 g, 85%) as a white solid.

Ethyl 5-methanesulfonyloxy hexanoate was prepared as previouslydescribed from ethyl-5-hydroxy-hexanoate (20.9 g, 130 mmol), mesylchloride (14.0 ml, 180 mmol) and diisopropylethylamine (27.2 ml, 157mmol) in 95% yield.

Ethyl 5-5-methanesulfonyloxy (33.3 g, 124 mmol), 2,4,6-triiodophenol(58.5 g, 124 mmol) and potassium carbonate (17.1 g, 124 mmol) werereacted in DMF (242 ml) at 82° C. as described for2-(4-iodophenoxy)decane. After stirring for 21 hrs, the reaction wasprocessed as for 2-(4-iodophenoxy)decane except at five times thevolumes to produce a viscous yellow oil (87.4 g). This product wasfurther purified by flash column chromatography (silica, hexanes) togive ethyl-5-(2,4,6-triiodophenoxy)hexanoate (40.0 g, 50.0%) as aviscous oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₁₇ I₃ O₃ : C,27.39; H, 2.79; I, 62.01. Found: C, 27.65, H, 2.72; I, 62.21.

EXAMPLE 30 5-(2,4,6-Triiodophenoxy)-hexan-1-ol ##STR33##

A flask containing ethyl 5-(2,4,6-triiodophenoxy)hexanoate (16.3 g, 26.5mmol) was charged with dry dichloromethane (133 ml). The reaction flaskwas fitted with an addition funnel, put under an atmosphere of N₂ andplaced in a dry ice/acetone bath. The addition funnel was charged with asolution of DiBAl-H in hexanes (1.0M, 58.5 ml, 58.5 mmol) which wasadded to the stirred reaction mixture over a period of 0.5 h. Afterstirring at -78° C. for 2.5 hrs, the addition funnel was charged withDiBAl-H solution (20 ml, 20 mmol) which was added to the reaction over aperiod of 0.25 hr. After stirring for 1 hr, the dry ice/acetone bath wasreplaced with an ice/water bath. After 1 hr, the dry ice/acetone bathwas replaced and the reaction was quenched by the slow addition of CH₃OH (5 ml). The reaction mixture was poured into a stirred mixture ofEtOAc (600 ml) and saturated aqueous Rochelle's salt (400 ml). Aftervigorously stirring for 3 hrs, the layers were separated. The organicphase was washed with saturated aqueous Rochelle's salt (250 ml) andbrine (250 ml), dried (Na₂ SO₄) and evaporated in vacuo to give a lightyellow residue (13.2 g). Recrystallization from EtOAc/hexanes provided5-(2,4,6-triiodophenoxy)-hexan-1-ol (12.6 g, 83%) as a white solid. Mp79°-80° C. (from ethylacetate/hexanes).

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₂ H₁₅ I₃ O₂ : C,25.20; H, 2.64; I, 66.56. Found: C, 25.31, H, 2.58; I, 66.81.

EXAMPLE 31 10-(4-Iodophenoxy)-undecan-1-ol ##STR34## A. Preparation of10-bromoundecan-1-ol

A flask containing 10-bromoundecanoic acid (25.0 g, 94.2 mmol) wascharged with dry THF (250 ml), immersed in an ice/water bath and fittedwith an addition funnel. The addition funnel was charged with borane-THFsolution (1.0M, 113 ml, 113 mmol) which was added to the stirredreaction mixture over a period of 45 minutes. 3 hrs after the additionwas completed, the reaction was poured into a stirred mixture of EtOAc(500 ml) and 10% aqueous potassium carbonate (300 ml). After vigorouslystirring for 0.5 hr, the layers were separated. The organic phase waswashed with water (250 ml) and brine (250 ml), dried (Na₂ SO₄), filteredand evaporated in vacuo. Flash column chromatography (silica, 1:4;EtOAc:hexanes) provided 10-bromo-undecan-1-ol (20.8 g, 88%).

B. Preparation of 10-(4-iodophenoxy)-undecan-1-ol

A reaction flask was charged with dry DMF (150 ml), 4-iodophenol (26.3g, 119 mmol) and potassium carbonate (16.5 g, 119 mmol), immersed in anoil bath and heated to 75° C. over a period of 0.5 hr. After stirring at75° C. for 0.5 hr, the reaction was fitted with an addition funnel whichwas charged with 10-bromoundecan-1-ol (20.0 g, 79.6 mmol) in a solutionof dry DMF (100 ml). The solution was added to the reaction mixture overa period of 14 hrs. The oil bath temperature was then increased to 90°C. After stirring for an additional 24 hrs, the reaction was allowed tocool, diluted with DMF, filtered through a pad of celite and evaporatedin vacuo. The resulting residue was taken up into EtOAc (750 ml), washedwith brine (300 ml), water (300 ml), 1M aqueous sodium hydroxide (300ml), water (300 ml) and brine (300 ml), dried (Na₂ SO₄), filtered andevaporated to provide a light brown residue (33.1 g). The product waspurified by repeated flash column chromatography (3×, silica, 1:9-1:4;EtOAc:hexanes) to provide 10-(4-iodophenoxy)-undecan-1-ol (12.1 g, 39%)as a light yellow oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₇ H₂₇ IO₂ :C,52.31; H, 6.97; I, 32.50. Found: C, 52.00, H, 6.93; I, 32.71.

EXAMPLE 32 Ethyl 5-(2,4,6-triiodophenoxy)hexyl carbonate ##STR35##

A flask containing 5-(triiodophenoxy)-hexan-1-ol (6.0 g, 10.5 mmol) wascharged with dry CH₂ Cl₂ (50 ml) and dry pyridine (9.6 ml, 105 mmol),placed under an atmosphere of N₂ and immersed in an ice/water bath.After 0.25 hr, ethyl chloroformate (8.1 ml, 105 mmol) was added over aperiod of 0.25 hrs via syringe. The reaction was allowed to stir withslow warming. After stirring for 4 hrs, the reaction was diluted withether (250 ml), washed with water (100 ml), 1M aqueous HCl (2×100 ml),water (2×100 ml) and brine (100 ml), dried (Na₂ SO₄), filtered andevaporated in vacuo. Flash column chromatography (silica, 1:9;EtOAc:hexanes) provided the product (6.49 g, 96%) as a light yellow oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₅ H₁₉ I₃ O₄ : C,27.97; H, 2.97; I, 59.11. Found: C, 28.06, H, 2.92; I, 58.92.

EXAMPLE 33 Ethyl 10-(3-iodophenoxy)-undecanoate ##STR36## A. Preparationof ethyl 10-bromoundecanoate

10-Bromoundecanoic acid (10.0 g, 87.7 mmol) obtained according to Rolla,F. and Landini, D., J. Org. Chem., 1980, 45, 3527-3529; Ashtor, R. andSmith, J. C., J. Chem. Soc., 1934, 435-440, was added to a stirredsolution of concentrated sulfuric acid (4 ml) in ethanol (155 ml). Thereaction flask was fitted with a reflux condenser and immersed in an oilbath which was brought to 120° C. over a 0.5 hr period. After refluxingfor 3 hrs, the reaction was allowed to cool and poured into ether (500ml). The ether was washed with saturated aqueous sodium bicarbonate(5×150 ml) and brine (2×150 ml), dried (Na₂ SO₄), filtered andevaporated in vacuo. Flash column chromatography (silica, 2.5% EtOAc inhexanes) provided ethyl 10-bromoundecanoate as a low melting solid.

B. Preparation of ethyl 10-(3-iodophenoxy)-undecanoate

To a stirred solution of ethyl 10-bromoundecanoate (9.7 g, 33.0 mmol) indry DMF (66 ml) was added 3-iodophenol (7.99 g, 36.3 mmol) and potassiumcarbonate (5.02 g, 37.6 mmol). The reaction was immersed in an oil bathwhich was warmed to 75° C. over 0.5 hr. After stirring for 14 hrs underan N₂ atmosphere, the oil bath temperature was increased to 85° C. Afterstirring for an additional 4 hrs at 85° C., the reaction was allowed tocool, diluted with DMF (200 ml), filtered through a pad of celite andevaporated in vacuo. The resulting residue was taken up in ether (500ml). The organic phase was washed with water (100 ml), 1M aqueous sodiumhydroxide (100 ml), water (2×100 ml) and brine (100 ml), dried (Na₂SO₄), filtered and evaporated in vacuo to provide crude ethyl10-(3-iodophenoxy)undecanoate which was contaminated with olefinicesters. Flash column chromatography (silica, 1-2%; EtOAc in hexanes)provide ethyl 10-(3-iodophenoxy)-undecanoate as a clear oil (4.75 g,33.3%).

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺ 432. Calculated forC₁₉ H₂₉ IO: C, 52.78; H, 6.77; I, 29.35. Found: C, 52.74, H, 6.77; I,29.26.

Compositions of the Present Invention

Compositions of the present invention comprise the followingpharmaceutically acceptable components:

    ______________________________________                                                                  More     Most                                                        Broad    Preferred                                                                              Preferred                                  Ingredients      Range    Range    Range                                      ______________________________________                                        Contrast agent   30-200   40-160   85-120                                     (mg I/ml of                                                                   total suspension)                                                             Cellulose derivative (% w/v)                                                                   0.05-10  0.1-4    0.2-1                                      Oily Vehicle (% w/v)                                                                           0.0-55   0.1-25   7-15                                       Surfactant (% w/v)                                                                             0.0-20   0.1-10   3-7                                        Viscosity modifying                                                                            0.0-15   0.001-4  0.05-1                                     excipients (% w/v)                                                            Water-q.s. to 100% by volume                                                  ______________________________________                                    

The contrast agent and the cellulose derivative blend is formulated foradministration using physiologically acceptable carriers or excipientsin a manner within the skill of the art. The contrast agent with theaddition of pharmaceutically acceptable aids (such as surfactants andemulsifiers) and excipients may be suspended or partially dissolved inan aqueous medium resulting in a solution, suspension or emulsion.

When the composition is used for CT imaging of the GI tract, theconcentration of the x-ray contrast agent should be in the range of from0.01 to 40 mg I/ml, more preferably of from 0.25 to 25 mg I/ml and mostpreferably of from 4-12 mg I/ml.

The preferred cellulose derivative utilized in the present invention isAVICEL® RC-591, which is a mixture of about 89 parts microcrystallinecellulose and about 11 parts of sodium carboxymethylcellulose.

In further reference to the components used in the compositions of thepresent invention the following should be noted.

The x-ray contrast agent present in concentrations lower than theabove-stated minimum in ibrmulations does not provide good quality x-rayor CT images, while concentrations above the above-maximum concentrationrender the GI tract too radiopaque and do not allow sufficientdelineation of the GI tract.

In practicing the present invention an oil-in-water emulsion ispreferred over a water-in-oil emulsion, suspension and dispersion. Oilymaterials, the density of which approximate the density of the aqueousphase impart stability to emulsions. For that reason low density oils,such as mineral oils, are desirable in preparing the emulsions. When thex-ray contrast agents are oily substances at room temperature, thepresence of an additional oily vehicle is not always necessary. Aboveabout 55% w/v of oil the emulsion is no longer an oil-in-water emulsionbut shifts to a water-in-oil emulsion.

Compositions without the presence of surfactants still provide excellentx-ray images, however, without surfactants the compositions are verydifficult to emulsify and only suspensions/dispersions are producedwhich are less desirable for coating the GI tract and are also lessstable on shelf-life. For reason of toxicity it is desirable to keep theconcentration of certain surfactants as low as possible; above about 20%w/v the risk of toxicity rapidly increases.

While the x-ray contrast agents of the present invention in formulationswith a pharmaceutically acceptable vehicle provide good quality x-rayimages, the addition of a cellulose derivative to the formulationsgreatly increases the quality of the x-ray images. At the low extreme ofthe concentration range there is little or no benefit gained, whileabove the higher extreme of the concentration range the emulsion is tooviscous for administration.

Depending on the form and amount of cellulose derivative used, additionsof viscosity modifying agents may not be necessary; at higher levelsthan about 15% w/v the viscosity is too high and gels will tend to form.

The following formulation examples will further illustrate theinvention.

    ______________________________________                                                              Amounts in % w/v                                        ______________________________________                                        Example 34                                                                    2,4,6-Triiodophenoxymethyleyelopentane                                                              14.50                                                   Light Mineral Oil, NF 12.50                                                   Polysorbate 80 (Tween 80)                                                                           3.37                                                    Sorbitan Mono-oleate (Span 80)                                                                      1.64                                                    AVICEL ® RC-591   0.50                                                    q.s. with water to 100% volume                                                Example 35                                                                    2-(4-Iodophenoxy)pentadecane                                                                        17.00                                                   Polysorbate 80 (Tween 80)                                                                           5.00                                                    AVICEL ® RC-591   6.50                                                    q.s. with water to 100% volume                                                Example 36                                                                    2-Iodophenoxycyclopentane                                                                           25.20                                                   Light Mineral Oil, NF 20.50                                                   Polysorbate 80 (Tween 80)                                                                           3.00                                                    AVICEL ® RC-591   0.15                                                    q.s. with water to 100% volume                                                ______________________________________                                    

The surface active agents may be cationic, anionic, nonionic,zwitterionic or a mixture of two or more of these agents.

Suitable cationic surfactants include cetyl trimethyl ammonium bromide.Suitable anionic agents include sodium lauryl sulphate, sodiumheptadecyl sulphate, alkyl benzenesulphonic acids and salts thereof,sodium butylnapthalene sulfonate, and sulphosuccinates. Zwitterionicsurface active agents are substances that when dissolved in water theybehave as diprotic acids and, as they ionize, they behave both as a weakbase and a weak acid. Since the two charges on the molecule balance eachother out they act as neutral molecules. The pH at which the zwitterionconcentration is maximum is known as the isoelectric point. Compounds,such as certain amino acids having an isoelectric point at the desiredpH of the formulations of the present invention are useful in practicingthe present invention.

In preparing the formulations of the present invention we prefer to usenonionic emulsifiers or surface active agents which, similarly to thenonionic contrast agents, possess a superior toxicological profile tothat of anionic, cationic or zwitterionic agents. In the nonionicemulsifying agents the proportions of hydrophilic and hydrophobic groupsare about evenly balanced. They differ from anionic and cationicsurfactants by the absence of charge on the molecule and, for thatreason, are generally less irritant than the cationic or anionicsurfactants. Nonionic surfactants include carboxylic esters, carboxylicamides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols.

One particular type of carboxylic ester nonionic surface active agentsare the partial, for example mono-, esters formed by the reaction offatty and resin acids, for example of about 8 to about 18 carbon atoms,with polyalcohols, for example glycerol, glycols such as mono-, di-,tetra- and hexaethylene glycol, sorbitan, and the like; and similarcompounds formed by the direct addition of varying molar ratios ofethylene oxide to the hydroxy group of fatty acids.

Another type of carboxylic esters are the condensation products of fattyand resin partial acids, for example mono-, esters ethylene oxide, suchas fatty or resin acid esters of polyoxyethylene sorbitan and sorbitol,for example polyoxyethylene sorbitan, mono-tall oil esters. These maycontain, for example, from about 3 to about 80 oxyethylene units permolecule and fatty or resin acid groups of from about 8 to about 18carbon atoms. Examples of naturally occurring fatty acid mixtures whichmay be used are those from coconut oil and tallow while examples ofsingle fatty acids are dodecanoic acid and oleic acid.

Carboxylic amide nonionic surface active agents are the ammonia,monoethylamine and diethylamine amides of fatty acids having an acylchain of from about 8 to about 18 carbon atoms.

The ethoxylated alkylphenol nonionic surface active agents includevarious polyethylene oxide condensates of alkylphenols, especially thecondensation products of mono-alkylphenols or dialkylphenols wherein thealkyl group contains about 6 to about 12 carbon atoms in either branchedchain or particularly straight chain configuration, for example, octylcresol, octyl phenol or nonyl phenol, with ethylene oxide, said ethyleneoxide being present in amounts equal to from about 5 to about 25 molesof ethylene oxide per mole of alkylphenol.

Ethoxylated aliphatic alcohol nonionic surface active agents include thecondensation products of aliphatic alcohols having from about 8 to 18carbon atoms in either straight chain or branched chain configuration,for example oleyl or cetyl alcohol, with ethylene oxide, said ethyleneoxide being present in equal amounts from about 30 to about 60 moles ofethylene oxide per mole of alcohol.

Preferred nonionic surface active agents include:

(a) Sorbitan esters (sold under the trade name Span) having the formula:##STR37## wherein R₁ =R₂ =OH, R₃ =R for sorbitan monoesters,

R₁ =OH, R₂ =R₃ =R for sorbitan diesters,

R₁ =R₂ =R₃ =R for sorbitan triesters,

where R=(C₁₁ H₂₃)COO for laurate, (C₁₇ H₃₃)COO for oleate, (C₁₅ H₃₁)COOfor palmitate, (C₁₇ H₃₅)COO for stearate;

(b) Polyoxyethylene alkyl ethers (i.e. Brijs) having the formula:

    CH.sub.3 (CH.sub.2).sub.x (O--CH.sub.2 --CH.sub.2).sub.y OH

where (x+1) is the number of carbon atoms in the alkyl chain, typically:

    ______________________________________                                        12 lauryl            (dodecyl)                                                14 myristyl          (tetradecyl)                                             16 cetyl             (hexadecyl)                                              18 stearyl           (octadecyl)                                              ______________________________________                                    

and y is the number of ethylene oxide groups in the hydrophilic chain,typically 10-60;

(c) Polyoxyethylene sorbitan fatty acid esters, sold under the tradenames of Polysorbates 20, 40, 60, 65, 80 & 85 having the formulas (1)and (2) ##STR38## wherein w+x+y+z=20 (Polysorbate 20, 40, 60, 65, 80 and85)

w+x+y+z=5 (Polysorbate 81)

w+x+y+z=4 (Polysorbate 21 and 61).

(d) Polyoxyethylene stearates, such as:

poly(oxy-1,2-ethanediyl),α-hydro-ω-hydroxy-octadecanoate;

polyethylene glycol monostearate; and

poly(oxy-1,2-ethanediyl)-α-(1-oxooctadecyl)-ω-hydroxypolyethylene glycolmonostearate.

The dosages of the contrast agent used according to the method of thepresent invention will vary according to the precise nature of thecontrast agent used. Preferably, however, the dosage should be kept aslow as is consistent with achieving contrast enhanced imaging. Byemploying as small amount of contrast agent as possible, toxicitypotential is minimized. For most contrast agents of the presentinvention dosages will be in the range of from about 0.1 to about 16.0 giodine/kg body weight, preferably in the range of from about 0.5 toabout 6.0 g iodine/kg of body weight, and most preferably, in the rangeof from about 1.2 to about 2.0 g iodine/kg body weight for regular x-rayvisualization of the GI tract. For CT scanning the contrast agents ofthe present invention will be in the range of from about 1 to about 600mg iodine/kg body weight, preferably in the range of from about 20 toabout 200 mg iodine/kg body weight, and most preferably in the range offrom about 40 to about 80 mg iodine/kg body weight.

When administered to mammals, the compositions of the present inventionproduce excellent x-ray and CT images.

The invention, having been fully described, it will be apparent to oneskilled in the art that changes and modifications can be made theretowithout departing from the spirit and scope thereof.

What is claimed is:
 1. An x-ray contrast composition for oral orretrograde examination of the gastrointestinal tract comprising:(a) fromabout 0.01 to 200 mg of iodine per ml of the composition of an x-raycontrast producing agent having the formula, or pharmaceuticallyacceptable salt thereof ##STR39## wherein Z is H, halo, C₁ -C₂₀ alkyl,cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groupscan be substituted with halogen or halo-lower-alkyl groups;R is methyl,ethyl, propyl, C₉ -C₂₅ alkyl, cycloalkyl, or halo-lower-alkyl,optionally substituted with halo, fluoro-lower-alkyl, aryl,lower-alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl orlower-alkoxy-carbonyloxy, (CR₁ R₂)_(p) --(CR₃ ═CR₄)_(m) Q, or (CR₁R₂)_(p) --C.tbd.C--Q; R₁, R₂, R₃ and R₄ are independently lower-alkyl,optionally substituted with halo; x is 1-4; n is 1-5; m is 1-15; p is1-10; and Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl,lower-alkylene, aryl, or aryl-lower alkyl; (b) from 0.05 to 10% w/v of acellulose derivative selected from the group consisting ofmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,hydroxyethyl methylcellulose, hydroxypropyl methylcellulose andmicrocrystalline cellulose; (c) from 0 to 55% w/v of an oily vehicle;(d) from 0 to 20% w/v of a surfactant selected from the group consistingof nonionic, anionic, cationic and zwitterionic surfactants; (e) from 0to 15% w/v of a viscosity modifying excipient; and (f) water to make100% by volume.
 2. The x-ray composition of claim 1 wherein said x-raycontrast producing agent is present in an amount of 30 to 200 mg ofiodine per ml of the composition.
 3. The x-ray contrast composition ofclaim 1 wherein said oily vehicle constitutes from 0.1 to 25% w/v of thecomposition.
 4. The x-ray contrast composition of claim 1 wherein saidsurfactant constitutes from 0.1 to 10% of the composition.
 5. The x-raycontrast composition of claim 1 wherein said microcrystalline cellulosehas an average particle size of from 0.01 to 100μ.
 6. The x-ray contrastcomposition of claim 5 wherein said microcrystalline cellulose is about89 parts microcrystalline cellulose and about 11 parts of sodiumcarboxymethylcellulose.
 7. The x-ray contrast composition of claim 1wherein said nonionic surface active agent is selected from the groupconsisting of carboxylic esters, carboxylic amides, ethoxylatedalklyphenols and ethoxylated aliphatic alcohols.
 8. The x-ray contrastcomposition of claim 1 wherein said surfactant is sorbitan ester havingthe formula: ##STR40## wherein R₁ =R₂ =OH, R₃ =R for sorbitanmonoesters,R₁ =OH, R₂ =R₃ =R for sorbitan diesters, R₁ =R₂ =R₃ =R forsorbitan triesters, where R=(C₁₁ H₂₃)COO for laurate, (C₁₇ H₃₃)COO foroleate, (C₁₅ H₃₁)COO for palmitate or (C₁₇ H₃₅)COO for stearate.
 9. Thex-ray contrast composition of claim 1 wherein said surface active agentis polyoxyethylene stearate.
 10. The x-ray contrast composition of claim1 wherein said surfactant is polyoxyethylene sorbitan fatty acid esterof the formulas (1) and (2) ##STR41## wherein w+x+y+z=20w+x+y+z=5w+x+y+z=4.
 11. An x-ray contrast composition for oral or retrogradeexamination of the gastrointestinal tract comprising:(a) from about 85to 120 mg of iodine per ml of the composition of an x-ray contrastproducing agent having the formula, or pharmaceutically acceptable saltthereof ##STR42## wherein Z is H, halo, C₁ -C₂₀ alkyl, cycloalkyl, loweralkoxy, cyano, where the alkyl and cycloalkyl groups can be substitutedwith halogen or halo-lower-alkyl groups;R is methyl, ethyl, propyl, C₉-C₂₅ alkyl, cycloalkyl, or halo-lower-alkyl, optionally substituted withhalo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy,lower-alkoxy carbonyl or lower-alkoxy-carbonyloxy, (CR₁ R₂)_(p) --(CR₃═CR₄)_(m) Q, or (CR₁ R₂)_(p) --C.tbd.C--Q; R₁, R₂, R₃ and R₄ areindependently lower-alkyl, optionally substituted with halo; x is 1-4; nis 1-5; m is 1-15; p is 1-10; and Q is H, lower-alkyl, lower-alkenyl,lower-alkynyl, lower-alkylene, aryl, or aryl-lower alkyl; (b) from 0.2to 1% w/v of a cellulose derivative selected from the group consistingof methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, hydroxyethyl methylcellulose, hydroxypropylmethylcellulose and microcrystalline cellulose; (c) from 7 to 15% w/v ofa mineral oil; (d) from 3 to 7% w/v of a surfactant selected from thegroup consisting of nonionic, anionic, cationic and zwitterionicsurfactants; (e) from 0.05 to 1% w/v of a viscosity modifying excipient;and (f) water to make 100% by volume.
 12. The x-ray contrast compositionof claim 11 wherein the average particle size of said microcrystallinecellulose is from 0.05 to 10μ.
 13. The x-ray contrast composition ofclaim 11 wherein said composition is in the form of an oil-in-wateremulsion.
 14. The x-ray contrast composition of claim 11 wherein saidx-ray producing agent is selected from the group consisting off2-(4-iodophenoxy)-decane, 2-(2,4,6-triiodophenoxy)-pentadecane,2-(2,4,6-triiodophenoxy)decane,(2,4,6-triiodophenoxy)-1H,1H,2H,2H-perfluorooctane,1-(2,4,6-triiodo-3-trifluorophenoxy)octane,2-(2,4,6-triiodophenoxy)-nonane, 2-ethyl-1-(2,4,6-triiodophenoxy)-hexaneand 3,3-diphenyl-1-(2,4,6-triiodophenoxy)propane.
 15. The x-ray contrastcomposition of claim 11 wherein said x-ray producing agent is selectedfrom the group consisting of: 3-(2,4,6-triiodophenoxy)-nonane,2-(4-iodophenoxy)-undecane, 2-iodophenoxycyclopentane,3-iodophenoxycyclopentane,(3,5-dimethyl-2,4,6-triiodophenoxy)cyclopentane,2-(4-iodophenoxy)-pentadecane, 4-iodophenoxycyclopentane,2,4,6-triiodophenoxycyclopentane, 2,4,6-triiodophenoxymethylcyclopentaneand 2-(2,4,6-triiodophenoxy)ethylcyclopentane.
 16. The x-ray contrastcomposition of claim 11 wherein said x-ray producing agent is selectedfrom the group consisting of:(E,E)-1-(2,4,6-triiodophenoxy)-3,7,11-trimethyl-2,6,10-dodecatriene,1-(2,4,6-triiodophenoxy)-3,7-dimethyl-6-octene,(E)-1-(3,5-dimethyl-2,4,6-triiodophenoxy)-3,7-dimethyl-2,6-octadiene and(E)-1-(2,4,6-triiodophenoxy)-3,7-dimethyl-2,6-octadiene.
 17. The x-raycontrast composition of claim 11 wherein said x-ray producing agent isselected from the group consisting of:1-(2,4,6-triiodophenoxy)-3-octyne, 2-(2,4,6-triiodophenoxy)-4-octyne,1-(2,4,6-triiodophenoxy)-3-octyne, diethyl2-(2,4,6-triiodophenoxy)-1,3-propanedioate and diisopropyl2-(2,4,6-triiodophenoxy)-1,3-propanedioate.
 18. The x-ray contrastcomposition of claim 11 wherein said x-ray producing agent is selectedfrom the group consisting of: ethyl 2,2-bis-(3-iodophenoxy)acetate,ethyl-5-(2,4,6-triiodophenoxy)-hexanoate,5-(2,4,6-triiodophenoxy)-hexan-1-ol, 10-(4-iodophenoxy)-undecan-1-ol,ethyl 5-(2,4,6-triiodophenoxy)-hexyl carbonate and ethyl10-(3-iodophenoxy)-undecanoate.
 19. A method of carrying out x-rayexamination of the gastrointestinal tract of a patient, said methodcomprises the oral or rectal administration to the patient an x-raycontrast formulation comprising:(a) from about 0.01 to 200 mg of iodineper ml of the composition of an x-ray contrast producing agent havingthe formula, or a pharmaceutically acceptable salt thereof ##STR43##wherein Z is H, halo, C₁ -C₂₀ alkyl, cycloalkyl, lower alkoxy, cyano,where the alkyl and cycloalkyl groups can be substituted with halogen orhalo-lower-alkyl groups;R is methyl, ethyl, propyl, C₉ -C₂₅ alkyl,cycloalkyl, or halo-lower-alkyl, optionally substituted with halo,fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxycarbonyl or lower-alkoxy-carbonyloxy, (CR₁ R₂)_(p) --(CR₃ ═CR₄)_(m) Q,or (CR₁ R₂)_(p) --C.tbd.C--Q; R₁, R₂, R₃ and R₄ are independentlylower-alkyl, optionally substituted with halo; x is 1-4; n is 1-5; m is1-15; p is 1-10; and Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl,lower-alkylene, aryl, or aryl-lower alkyl; (b) from 0.05 to 10% w/v of acellulose derivative selected from the group consisting ofmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,hydroxyethyl methylcellulose, hydroxypropyl methylcellulose andmicrocrystalline cellulose; (c) from 0 to 55% w/v of an oily vehicle;(d) from 0 to 20% w/v of a surfactant selected from the group consistingof nonionic, anionic, cationic and zwitterionic surfactants; (e) from 0to 15% w/v of a viscosity modifying excipient; and (f) water to make100% by volume.
 20. The method of claim 19 wherein said x-ray producingagent is selected from the group consisting of:2-(4-iodophenoxy)-decane, 2-(2,4,6-triiodophenoxy)-pentadecane,2-(2,4,6-triiodophenoxy)decane,(2,4,6-triiodophenoxy)-1H,1H,2H,2H-perfluorooctane,1-(2,4,6-triiodo-3-trifluorophenoxy)octane,2-(2,4,6-triiodophenoxy)-nonane, 2-ethyl-1-(2,4,6-triiodophenoxy)-hexaneand 3,3-diphenyl-1-(2,4,6-triiodophenoxy)propane.
 21. The method ofclaim 19 wherein said x-ray producing agent is selected from the groupconsisting of: 3-(2,4,6-triiodophenoxy)-nonane,2-(4-iodophenoxy)-undecane, 2-iodophenoxycyclopentane,3-iodophenoxycyclopentane,(3,5-dimethyl-2,4,6-triiodophenoxy)cyclopentane,2-(4-iodophenoxy)-pentadecane, 4-iodophenoxycyclopentane,2,4,6-triiodophenoxycyclopentane, 2,4,6-triiodophenoxymethylcyclopentaneand 2-(2,4,6-triiodophenoxy)ethylcyclopentane.
 22. The method of claim19 wherein said x-ray producing agent is selected from the groupconsisting off(E,E)-1-(2,4,6-triiodophenoxy)-3,7,11-trimethyl-2,6,10-dodecatriene,1-(2,4,6-triiodophenoxy)-3,7-dimethyl-6-octene,(E)-1-(3,5-dimethyl-2,4,6-triiodophenoxy)-3,7-dimethyl-2,6-octadiene and(E)-1-(2,4,6-triiodophenoxy)-3,7-dimethyl-2,6-octadiene.
 23. The methodof claim 19 wherein said x-ray producing agent is selected from thegroup consisting of: 1-(2,4,6-triiodophenoxy)-3-octyne,2-(2,4,6-triiodophenoxy)-4-octyne, 1-(2,4,6-triiodophenoxy)-3-octyne,diethyl 2-(2,4,6-triiodophenoxy)-1,3-propanedioate and diisopropyl2-(2,4,6-triiodophenoxy)-1,3-propanedioate.
 24. The method of claim 19wherein said x-ray producing agent is selected from the group consistingof: ethyl 2,2-bis-(3-iodophenoxy)acetate,ethyl-5-(2,4,6-triiodophenoxy)-hexanoate,5-(2,4,6-triiodophenoxy)-hexan-1-ol, 10-(4-iodophenoxy)-undecan-1-ol,ethyl 5-(2,4,6-triiodophenoxy)-hexyl carbonate and ethyl10-(3-iodophenoxy)-undecanoate.